Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113965 - 113965

Published: March 1, 2024

G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits assembly and interacts with via an ITFG motif, residue F17, the N protein. Prior studies examining impact G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, role this pathogenesis is unknown. Here, we use structural biochemical analyses define residues required for G3BP1-N structure-guided mutagenesis selectively disrupt interaction. We find N-F17A mutation causes highly specific loss G3BP1/2. fails inhibit cells, has decreased replication, pathology vivo. Further mechanistic indicate N-F17-mediated promotes infection by limiting sequestration genomic RNA (gRNA) into granules.

Language: Английский

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Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 20, 2024

Language: Английский

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Human Coronavirus OC43 as a Low-Risk Model to Study COVID-19

Viruses, Journal Year: 2023, Volume and Issue: 15(2), P. 578 - 578

Published: Feb. 20, 2023

The coronavirus disease 2019 (COVID-19) pandemic has had irreversible and devastating impacts on every aspect of human life. To better prepare for the next similar pandemic, a clear understanding biology is prerequisite. Nevertheless, high-risk nature causative agent COVID-19, severe acute respiratory syndrome 2 (SARS-CoV-2), requires use cumbersome biosafety level-3 (BSL-3) confinement facility. facilitate development preventive therapeutic measures against SARS-CoV-2, one endemic strains low-risk coronaviruses gained attention as useful research alternative: OC43 (HCoV-OC43). In this review, its history, classification, clinical manifestations are first summarized. characteristics viral genomes, genes, evolution process then further explained. addition, host factors necessary to support life cycle HCoV-OC43 innate, well adaptive, immunological responses infection discussed. Finally, in vitro vivo systems study application discovery potential antivirals COVID-19 by using models also presented. This review should serve concise guide those who wish setting.

Language: Английский

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Multiple functions of stress granules in viral infection at a glance

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: March 1, 2023

Stress granules (SGs) are distinct RNA induced by various stresses, which evolutionarily conserved across species. In general, SGs act as a conservative and essential self-protection mechanism during stress responses. Viruses have long evolutionary history viral infections can trigger series of cellular responses, may interact with SG formation. Targeting is believed one the critical measures for viruses to tackle inhibition host cells. this systematic review, we summarized role in infection categorized their relationships into three tables, particular focus on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Moreover, outlined several kinds drugs targeting according different pathways, most potentially effective against SARS-CoV-2. We believe review would offer new view researchers clinicians attempt develop more efficacious treatments virus infection, particularly treatment SARS-CoV-2

Language: Английский

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The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(2), P. 902 - 926

Published: Jan. 2, 2024

Language: Английский

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The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target

Antiviral Research, Journal Year: 2024, Volume and Issue: 228, P. 105921 - 105921

Published: May 31, 2024

Language: Английский

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Influenza A virus NS1 effector domain is required for PA-X-mediated host shutoff in infected cells

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(5)

Published: April 17, 2024

ABSTRACT Many viruses inhibit general host gene expression to limit innate immune responses and gain preferential access the cellular translational apparatus for their protein synthesis. This process is known as shutoff. Influenza A (IAVs) encode two shutoff proteins: nonstructural 1 (NS1) polymerase acidic X (PA-X). NS1 inhibits nuclear pre-messenger RNA maturation export, PA-X an endoribonuclease that preferentially cleaves spliced cytoplasmic messenger RNAs. Emerging evidence suggests in circulating human IAVs co-evolve ensure optimal magnitude of without compromising viral replication relies on cell metabolism. However, functional interplay between remains unexplored. In this study, we sought determine whether function has a direct effect activity by analyzing A549 cells infected with wild-type or mutant effector domain deletion. was done using conventional quantitative reverse transcription chain reaction techniques sequencing nanopore technology. Our previous research molecular mechanisms identified prominent features IAV-infected cells: accumulation poly(A) binding (PABPC1) increase abundance relative cytoplasm. Here demonstrate augments necessary PABPC1 accumulation. By contrast, not dependent either PA-X-mediated accompanied retention transcripts. study demonstrates first time may functionally interact mediating IMPORTANCE Respiratory including influenza virus continue cause annual epidemics high morbidity mortality due limited effectiveness vaccines antiviral drugs. Among strategies evolved evade shutoff—a blockade Disabling being explored live attenuated vaccine development attractive strategy increasing boosting responses. encodes proteins shutoff: We others have characterized some action additive effects these ensuring expression. work, examined discovered required effectively. work significantly advances our understanding identifies new potential targets therapeutic interventions against further informs improved vaccines.

Language: Английский

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A closer look at mammalian antiviral condensates

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(3), P. 1393 - 1404

Published: May 23, 2024

Several biomolecular condensates assemble in mammalian cells response to viral infection. The most studied of these are stress granules (SGs), which have been proposed promote antiviral innate immune signaling pathways, including the RLR-MAVS, protein kinase R (PKR), and OAS-RNase L pathways. However, recent studies demonstrated that SGs either negatively regulate or do not impact signaling. Instead, SG-nucleating protein, G3BP1, may function perturb RNA biology by condensing into viral-aggregated condensates, thus explaining why viruses often antagonize G3BP1 hijack its function. a recently identified condensate, termed double-stranded RNA-induced foci, promotes activation PKR In addition, SG-like known as an RNase L-induced bodies (RLBs) observed during many infections, SARS-CoV-2 several flaviviruses. RLBs promoting decay cellular RNA, well ribosome-associated Herein, we review advances field provide perspective on role canonical response.

Language: Английский

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Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 212 - 212

Published: Jan. 31, 2024

Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is inhibition integrated stress response—the mechanism through which infected cells arrest translation phosphorylation alpha subunit eukaryotic initiation factor 2 (eIF2α). We have recently shown that human common cold betacoronavirus OC43 actively inhibits eIF2α in response sodium arsenite, a potent inducer oxidative stress. In this work, we examined modulation responses by and demonstrated negative feedback regulator GADD34 strongly induced cells. However, upregulation expression was independent from activation not required for virus-infected Our work reveals complex interplay between coronavirus response, viral protein ensured but loop disrupted.

Language: Английский

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DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

ABSTRACT The SARS-CoV-2 pandemic and the emergence of novel variants underscore need to understand host-virus interactions identify host factors that restrict viral infection. Here, we perform a genome-wide CRISPR knockout screen restriction for SARS-CoV-2, revealing DAZAP2 as potent antiviral gene. DAZAP2, previously implicated in restriction, is found inhibit entry by blocking virion fusion with both endolysosomal plasma membranes. Additionally, suppresses genomic RNA replication without affecting primary translation replicases. We demonstrate functions pan-coronavirus factor across four genera coronaviruses. Importantly, enhances infection mouse models human airway epithelial cells, confirming its physiological relevance. Mechanistically, activity appears be indirect, potentially through regulation gene expression, it primarily localizes nucleus. Our findings provide new insights into defense system against coronaviruses highlight potential target host-directed therapies. IMPORTANCE During infection, response mediated variety distinct mechanisms have yet fully elucidated. Although was action vivo relevance remain unclear. In this study, inhibits dual mechanisms: membranes, suppressing replication. confirm using cell cultures. This study advances our understanding host-pathogen interactions. Targeting or regulatory pathways could approach enhance current future coronavirus threats.

Language: Английский

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